Pharmacokinetics of pimecrolimus in infants

Initial safety concerns were related to the potential systemic absorption of pimecrolimus. However, evidence from experiments in minipigs showed that the systemic bioavailability of pimecrolimus was transient and negligible, making the risk for systemic side effects not relevant (59). Furthermore, the penetration and permeation profile of pimecrolimus was superior compared to other treatments for AD. Whereas drug concentrations of pimecrolimus in human skin were of the same order of magnitude as tacrolimus and TCS, permeation was 9-10 and 70-110 fold lower than tacrolimus and TCS, respectively, predicting lower systemic exposure (60). The pharmacokinetic (PK) profile of pimecrolimus was evaluated in six studies, which enrolled a total of 41 infants treated with pimecrolimus for 3 weeks (Table 2) . Pimecrolimus blood concentrations were below the limit of quantification (LoQ) in the majority of samples, which was either 0.1 or 0.5 ng/mL, depending on the assay used (61-65). In the remaining blood samples, the blood concentration of pimecrolimus was below 2 ng/mL, with some exceptional outliers that were just above this limit. One study evaluated blood samples of infants aged between 5.7-11.9 months over a 1-year period of intermittent pimecrolimus treatment (63). Importantly, this study found no accumulation of pimecrolimus in infants with moderate-to-severe AD, consistently showing minimal systemic exposure even on the long-term. The impact of the total body surface area (TBSA) affected was also found to be minimal, and the difference between patients with 90% and 10% of TBSA affected was not greater than 0.74 ng/mL (62). These findings were also supported by another study, which enrolled infants with a maximum TBSA affected of 92%, but systemic pimecrolimus concentrations remained below 2.26 ng/mL in all infants after 3 weeks of treatment (65). These concentrations are far below the maximum blood concentration (54.5 ng/mL) observed in adult patients with psoriasis treated orally with 30 mg twice daily of pimecrolimus for 4 weeks, a dose that was also well-tolerated in these patients (62). An analysis of pimecrolimus blood concentrations in infants compared to older children (>24 months of age) demonstrated that infants were not a higher risk for systemic exposure of pimecrolimus, and that blood concentrations of pimecrolimus remained below the LoQ (i.e. <0.5 ng/mL) in the majority of patients, irrespective of age (66). Overall, the favorable penetration and permeation profile of pimecrolimus seen in minipigs together with the minimal systemic exposure found in the PK studies support that use of pimecrolimus in infants is safe, regardless of the TBSA affected and duration of treatment.